Mitochondrial function is integral to normal homeostasis and cell survival, which are optimally mediated by efficient conversion of substrate fuel into ATP and by precise coordination of nuclear and mitochondrial genomes. Mitochondrial function has been implicated in the etiopathology of such diverse conditions as aging, apoptosis, necrosis and other acquired and congenital diseases. See, e.g., Schon, E. A., Trends Biochem. Sci. 25:555-560 (2000); Orth, M. and Schapira, Am. J. Med. Genet., 106:27-36 (2001); Wallace, D. C., Ment. Retard. Dev. Disabil. Res. Rev. 7:158-166 (2001).
One determinant of mitochondrial energetics is the activity of pyruvate dehydrogenase complex (PDC), which is entirely nuclear-encoded and comprises three functionally independent enzymes. PDC catalyzes the rate-determining step in aerobic carbohydrate metabolism and mediates conversion of fuel into energy. PDC activity, in turn, is regulated by reversible phosphorylation (inactivation) of its E1 alpha subunit. PDC deficiency is associated with a number of diseases and disorders. Congenital defects in PDC are typically due to mutations in E1α, typified by lactic acidosis, neurodegeneration and early death. Acquired deficiencies in PDC have been associated with other metabolic or neurodegenerative disorders.
PDC is regulated, in part, by reversible phosphorylation wherein the phosphorylated enzyme complex is inactive. Phosphorylation of certain residues is mediated by pyruvate dehydrogenase kinase (PDK). More specifically, phosphorylation of serine residues on the E1α subunit renders the PDC inactive. Thus, compounds that inhibit PDK block the phosphorylation of PDC resulting in greater amounts of the enzyme in its unphosphorylated, active state.
Numerous disorders caused solely or in part by abnormal regulation of PDC in including humans remain unmet with regard to treatment agents and protocols. As such, agents and therapeutic methods capable of stimulating the activity of PDC, including e.g., inhibition of PDK or increasing expression of PDC, are relevant for amelioration of diseases, disorders, or symptoms thereof that are mediated by abnormal PDC regulation.